Nitroxides (lead compound, Tempol), which are potent antioxidants, are proving to have broad utility in a number of disease processes and/or conditions that represent excessive oxidative stress. The fact that nitroxides exert activity over such a range of disease conditions speaks to the importance of free radical reactions in tissue. Likewise, it is becoming apparent that free radicals are important in normal molecular signaling pathways and related gene expression. We have further demonstrated that Tempol application can provide protection of normal tissues exposed to radiation. Using a miniature pig (minipig) model for irradiation-induced oral mucositis, animals were exposed to daily fractionated radiation (5 x 6 Gy), where the nitroxide Tempol was administered i.p. 10 min before each radiation fraction. Tempol provided protection against radiation-induced mucositis and ulceration. These findings are consistent with mouse studies conducted recently showing comparable radioprotective effects. We have also finished studies evaluating Tempol to reduce the severity and progression of multiple sclerosis (MS). Several reactive oxygen (ROS) and reactive nitrogen species (RNS) are implicated in inflammatory-mediated damage to the central nervous system (CNS) in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of these studies was to investigate the immunomodulatory effects and therapeutic potential of orally-delivered Tempol in the mouse EAE model. Mice receiving TEMPOL chow ad libitum for 2weeks prior to induction of active EAE showed delayed onset and reduced incidence of disease compared to control-fed animals. Reduced disease severity was associated with limited microglial activation and fewer inflammatory infiltrates. Tempol's effects were immunomodulatory, not immunosuppressive: T cells produced less interferon-gamma and tumor necrosis factor-alpha. TEMPOL administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+ regulatory populations. Tempol treatment also reduced the severity of clinical disease when administered after the induction of disease, and also after the onset of clinical symptoms. The ability of oral TEMPOL to reduce inflammation and axonal damage and loss demonstrate both anti-inflammatory and protective properties, with significant promise for the treatment of MS and related neurological disorders.